Rapid tumor growth is accompanied by an unbalance between oxygen supply and consumption resulting in low oxygen levels and thus the existence of hypoxic regions. Tumor hypoxia is not only the major problem for radiotherapy treatment failure and anticancer drug resistance, but also an indicator for advanced disease stages, disease relapse and poor prognosis (J. M. Brown, Cancer Res., 1999, 59, 5863-5870). The transcription factor HIF-1 (Hypoxia-inducible factor-1) plays a significant role in cellular adaption and survival under hypoxic condition (D. G. Nagle and Y. D. Zhou, Curr. drug targets, 2006, 7, 355-369). Preclinical studies indicate that the inhibition of HIF-1 activity has a remarkable impact on tumor growth (G. L. Semenza, Nat. Rev. Cancer, 2003, 3, 721-732). Besides, combination of HIF-1 inhibition with chemotherapeutic agents/radiation gives rise to improved treatment outcomes (Li, L. et al., Clin. Cancer Res., 2006, 12, 4747-4754, Moeller, B. J. et al., Cancer Cell, 2005, 8, 99-110). Consequently, HIF-1 represents a promising target for cancer therapy. Presently, early phase clinical trials with topotecan, a natural product-derived topoisomerase-1/HIF-1 inhibitor, have been completed. Moreover, digoxin has entered phase two clinical trial as novel HIF-1 inhibitor, which exhibits the prospect of developing HIF-1 targeted anticancer drugs.
There remains a strong need for therapeutically effective compounds and improved ways for successfully treating cancer, wherein inhibiting HIF-1 represents a highly promising approach as explained above. As usual, it would generally be desirable to have compounds with reduced risk for side effects, which can be prepared in a cost-effective way and are directed only at tumor cells.
Recently, Traditional Chinese medicine as well as complementary and alternative medicine has getting popular providing a lot of treatment options. Traditional Chinese medicines based on plant materials as well as plants or respective components gained from plants usually allow for treatment of various diseases and conditions while bearing a reduced risk for side effects. In view of the rich medicinal plant resources, available respective medicines can usually be produced in a cost-effective way. Accordingly, there has been a lot of research with regard to plants and respective ingredients for treatment of several diseases and conditions.
For example, Tylophora atrofolliculata (Asclepiadaceae) is already used as a traditional medicine. The roots of Tylophora atrofolliculata which are mainly distributed in the Guangxi Province in the Southwest of China have been used such as for the treatment of rheumatism. Components isolated from said plant include phenanthroindolizidine alkaloids (Huang, X. et al., Planta Med., 2004, 70, 441-445, Abe, F. et al., Chem. Pharm. Bull, 1998, 46, 767-769, Abe, F. et al., Phytochemistry, 1995, 39, 695-699, Ali, M. et al., J. Nat. Prod., 1991, 54, 1271-1278, M. Ali and K. K. Bhutani, Phytochemistry, 1987, 26, 2089-2092, Ali, M. and Bhutani, K. K., Phytochemistry, 1989, 28, 3513-3517, Bhutani, K. K. et al., Phytochemistry, 1985, 24, 2778-2780, Dhiman, M. et al., Chem. Pap.-Chem. Zvesti, 2013, 67, 245-248), however, only alkaloids such as tylophoridicine C-F, tylophorinine, tylophorinidine have been isolated from this plant so far. Members of the phenanthroindolizidine alkaloid class are generally well known to possess multiple pharmacological effects, such as anti-inflammatory, antifungal, antibacterial, and antiviral activities. Besides, pronounced cytotoxicity of some phenanthroindolizidine alkaloids against various cancer cell lines attracted much attention in the discovery of anticancer drugs (Lee, Y. Z. et al., Planta Med., 2011, 77, 1932-1938, Cai, X. F. et al., J. Nat. Prod., 2006, 69, 1095-1097, Damu, A. G. et al., Planta Med., 2009, 75, 1152-1156, Damu, A. G. et al., J. Nat. Prod., 2005, 68, 1071-1075, Lykkeberg, A. K. et al., J. Nat. Prod., 2002, 65, 1299-1302).
In view of the presence of various different compounds in plants usually with completely different mode of action and therapeutic efficiency, there is a strong need for identifying and providing components in isolated form with suitable therapeutic efficiency such as with sufficient HIF-1 inhibitory activity for treatment of cancer. Having those active ingredients in isolated form could further reduce the risk of side effects or interactions resulting from the presence of further compounds limiting the therapeutic use.